Safety and Efficacy of Nivolumab Plus Ipilimumab in Microsatellite Instability-High/Mismatch Repair-Deficient Colorectal Cancer: A Systematic Review.

AIMS: Colorectal cancer (CRC) remains a significant global health burden, with rising incidence and mortality despite advances in screening and treatment. Microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) CRCs comprise a distinct molecular subtype characterised by a high mutational burden and immunogenicity, rendering them responsive to immune checkpoint inhibitors. The combination of nivolumab (anti-programmed cell death protein 1 [PD-1]) and ipilimumab (anti-CTLA-4) has emerged as a promising therapeutic strategy. This systematic review aims to evaluate the safety and efficacy of nivolumab plus ipilimumab combination therapy in patients with MSI-H/dMMR CRC. MATERIALS AND METHODS: A literature search was conducted across PubMed, Embase, Cochrane Library, Web of Science, and Scopus up to March 2025. Eligible studies included clinical trials or observational studies that reported efficacy (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and safety outcomes (treatment-related adverse events [TRAEs]) of nivolumab plus ipilimumab combination therapy in MSI-H/dMMR CRC. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool and the Newcastle-Ottawa Scale. RESULTS: Six studies (N = 758) were included: four phase II trials, one phase III randomised trial, and one phase II neoadjuvant trial. Participants were predominantly White, with a median age of 56.5-66 years, and most had right-sided tumours. Across studies, nivolumab plus ipilimumab combination therapy demonstrated favourable ORRs (31-69%), durable PFS, and OS benefits, particularly in metastatic settings. Neoadjuvant use also showed a promising pathologic response. TRAEs were generally manageable; grade 3-4 events occurred in 14-35% of patients, commonly diarrhoea, fatigue, and endocrinopathies. CONCLUSION: Nivolumab plus ipilimumab is an effective and relatively well-tolerated option for MSI-H/dMMR CRC, offering significant clinical benefit across disease stages. Ongoing trials and longer follow-up are warranted to optimise dosing, identify predictive biomarkers, and refine patient selection.